Biochemistry. 2022 Jun 22. doi: 10.1021/acs.biochem.2c00042. Online ahead of print.

ABSTRACT

The two RNA-dependent RNA polymerase inhibitors remdesivir and favipiravir were originally developed and approved as broad-spectrum antiviral drugs for the treatment of harmful viral infections such as Ebola and influenza. With the outbreak of the global SARS-CoV-2 pandemic, the two drugs were repurposed for the treatment of COVID-19 patients. Clinical studies suggested that the efficacy of the drugs is enhanced in the case of an early or even prophylactic application. Because the contact between drug molecules and the plasma membrane is essential for a successful permeation process of the substances and therefore for their intracellular efficiency, drug-induced effects on the membrane structure are likely and have already been shown for other substances. We investigated the impact of remdesivir and favipiravir on lipid bilayers in model and cell membranes via several biophysical approaches. The measurements revealed that the embedding of remdesivir molecules in the lipid bilayer results in a disturbance of the membrane structure of the tested phospholipid vesicles. Nevertheless, in a cell-based assay, the presence of remdesivir induced only weak hemolysis of the treated erythrocytes. In contrast, no experimental indication for an effect on the structure and integrity of the membrane was detected in the case of favipiravir. Regarding potential prophylactic or accompanying use of the drugs in the therapy of COVID-19, the physiologically relevant impacts associated with the drug-induced structural modifications of the membrane might be important to understand side effects and/or low effectivities.

PMID:35731976 | DOI:10.1021/acs.biochem.2c00042

HIV Med. 2022 Jun 22. doi: 10.1111/hiv.13352. Online ahead of print.

ABSTRACT

INTRODUCTION: HIV programmes across many countries in Africa have recently transitioned people living with HIV from efavirenz (EFV)- to dolutegravir (DTG)-containing antiretroviral therapy (ART). As both drugs are associated with neuropsychiatric adverse effects, this study assessed the mental health and HIV/ART-associated symptoms of people living with HIV before and after transition to DTG.

METHODS: The prospective DO-REAL cohort enrolled people starting DTG-based ART in Lesotho from February to December 2020. For this analysis within DO-REAL, we included adults changing from tenofovir disoproxil fumarate (TDF)/lamivudine (3TC)/EFV to TDF/3TC/DTG within first-line therapy. At transition and 16 weeks thereafter, participants completed the Patient Health Questionnaire-9 (PHQ-9; depression screening), the 12-item Short-Form Health Survey (SF-12; mental and physical health), and a modified HIV Symptom Index (mHSI; HIV/ART-related symptoms). We also assessed weight change. We used McNemar tests with Bonferroni corrections to assess binary outcomes.

CLINICALTRIALS: gov: NCT04238767.

RESULTS: Among 1228 participants, 1131 completed follow-up. Of these, 60.0% were female, the median age was 46 years (interquartile range [IQR] 38-55), and the median time taking ART was 5.7 years (IQR 3.5-8.9). No change was observed for weight or overall PHQ-9 or SF-12 outcomes. However, three mHSI items decreased at follow-up: 'feeling sad/down/depressed' (bothered 6.0% vs. 3.3% of participants at least 'a little' before vs. after transition; adjusted p = 0.048); 'feeling nervous/anxious' (7.4% vs. 3.4%; adjusted p = 0.0009); and 'nightmares, strange/vivid dreams' (6.3% vs. 3.5%; adjusted p = 0.027). Individual PHQ-9 or SF-12 items also improved. Being symptom free across all measures increased from 5.1% to 11.4% (p < 0.0001).

CONCLUSIONS: We observed no negative impacts and potential moderate improvements with DTG, providing further support for the rollout of DTG.

PMID:35730213 | DOI:10.1111/hiv.13352

J Oncol Pharm Pract. 2022 Jun 22:10781552221110472. doi: 10.1177/10781552221110472. Online ahead of print.

ABSTRACT

INTRODUCTION: Drug-induced crystalline maculopathy has been reported secondary to tamoxifen use for breast cancer treatment. It could be misdiagnosed as macular telangiectasia type 2 (MacTel type 2).

CASE REPORT: A 56-year-old woman with a history of diabetes mellitus and breast cancer was referred to our clinic with painless, bilateral, gradual onset of central vision loss for several months. The fundus examination showed the macular pigmentary change in both eyes and a few refractile crystalline deposits in the parafoveal area in the left eye. However, the rest of the retina was normal in both eyes.

MANAGEMENT AND OUTCOME: With the diagnosis of tamoxifen-induced maculopathy, the drug was discontinued and supplementary treatment was started.

DISCUSSION: In this report, patient medical and drug history was an important and powerful measure. Due to the side effects of long-term use of tamoxifen, we need further studies on the need for retinal screening in these patients.

PMID:35730198 | DOI:10.1177/10781552221110472

Integr Cancer Ther. 2022 Jan-Dec;21:15347354221105563. doi: 10.1177/15347354221105563.

ABSTRACT

BACKGROUND: Complementary and Alternative Medicine (CAM) is widely used around the world to treat adverse effects derived from cancer treatment among children and young adults. Parents often seek CAM to restore and maintain the child's physical and emotional condition during and after cancer treatment.

OBJECTIVES: The objectives of this review were (i) to identify literature that investigates CAM use for treating adverse effects of conventional cancer treatment, (ii) to investigate the safety of the included CAM modalities, and (iii) to evaluate the quality of included studies.

METHODS: Five scientific research databases were used to identify observational, quasi-experimental, and qualitative studies from January 1990 to May 2021. Included studies investigated the use of CAM to treat adverse effects of cancer treatment in childhood cancer.

RESULTS: Fifteen studies were included in this review. Ten quasi-experimental, 3 observational studies (longitudinal/prospective), 2 qualitative studies, and 1 study with a quasi-experimental and qualitative arm were identified. Less than half (n = 6; 40%) of the studies included reported adverse effects for the CAM modality being studied. Among the studies that reported adverse effects, they were mostly considered as direct risk, as 13% reported mainly bleeding and bruising upon acupuncture treatment, and dizziness with yoga treatment. All adverse effects were assessed as minor and transient. CAM modalities identified for treating adverse effects of cancer treatment were alternative medical systems, manipulative and body-based therapies, biologically-based therapies, and mind-body therapies. CAM modalities were used to alleviate anxiety, pain, toxicity, prevent trauma, and improve health-related quality of life, functional mobility, and physical activity levels. All studies assessed scored 70% or above according to the Joanna Briggs Institute critical appraisal for study quality checklists.

CONCLUSION: Most of the studies (58.3%) included in this review did not report adverse effects from CAM modalities used to treat adverse effects of cancer treatment in children and young adults. This lack of safety information is of concern because parents need to know whether the modality represents an extra burden or harm to the child. To improve awareness about safety in the field, a universal and uniform reporting system for adverse effects in CAM research is needed.

PMID:35726681 | DOI:10.1177/15347354221105563

Respir Res. 2022 Jun 21;23(1):164. doi: 10.1186/s12931-022-02082-x.

ABSTRACT

BACKGROUND: Rituximab (RTX) has been previously reported as directed treatment in patients with connective-tissue disease-related interstitial lung diseases (CTD-ILD). A systematic assessment of treatment effect size on pulmonary function outcomes and related adverse effects in patients with CTD-ILD has not been previously reported.

METHODS: We performed a systematic review and meta-analysis of published reports from PubMed, Embase, and Cochrane Libraries. Randomized and non-randomized controlled trials, case-control, cohort, and case series (with five or more cases) containing individual pulmonary function data and adverse effects were included. Study endpoints were pre- and post-treatment change in percent predicted forced vital capacity (FVC %) and diffusion capacity for carbon monoxide (DLCO%), along with reported drug-related adverse events.

RESULTS: Twenty studies totaling 411 patients were identified with 14 included in the meta-analysis of pulmonary function and six in the descriptive review. Random effects meta-analysis of pre- and post-treatment pulmonary function findings demonstrated increases in FVC% (n = 296) (mean difference (MD) 4.57%, [95% CI 2.63-6.51]) and DLCO% (n = 246) (MD 5.0% [95% CI 2.71-7.29]) after RTX treatment. RTX treatment-related adverse effects were reported in 13.6% of the pooled cohort.

CONCLUSIONS: A systematic assessment of post-treatment effect size suggests a potential role for RTX in stabilizing or improving lung function in patients with CTD-ILD, with a modest but not insignificant adverse effect profile.

PMID:35729565 | DOI:10.1186/s12931-022-02082-x

Eur J Hosp Pharm. 2022 Jun 21:ejhpharm-2022-003333. doi: 10.1136/ejhpharm-2022-003333. Online ahead of print.

ABSTRACT

BACKGROUND: The baseline incidence of the adverse events of statin therapy varies between countries. Notably, Chinese patients seem more susceptible to myopathy induced by simvastatin.

OBJECTIVES: This research studies the adverse drug reactions (ADRs) of statin therapy in China by analysing trial-based data from the Anti-hyperlipidaemic Drug Database built by the China National Medical Products Administration Information Centre.

METHODS: All clinical trials involving statin therapy (including simvastatin, atorvastatin, fluvastatin, lovastatin, pravastatin and rosuvastatin) in China from 1989 to 2019 were screened. In total, 569 clinical studies with 37 828 patients were selected from 2650 clinical trials in the database.

RESULTS: Among the reported cases with ADRs (2822/37 828; 7.460%), gastrointestinal symptoms were the most common (1491/37 828; 3.942%), followed by liver disease (486/37 828; 1.285%), muscle symptoms (444/37 828; 1.174%) and neurological symptoms (247/37 828; 0.653%). Pravastatin (231/1988; 11.620%) caused the most common gastrointestinal side effects, followed by fluvastatin (333/3094; 10.763%). The least likely to cause gastrointestinal irritation was rosuvastatin (82/1846; 4.442%).

CONCLUSION: In Chinese clinical trials, gastrointestinal symptoms were the most common ADR of statin use for hyperlipidaemia and other cardiovascular diseases.

PMID:35728952 | DOI:10.1136/ejhpharm-2022-003333

Eur J Hosp Pharm. 2022 Jun 21:ejhpharm-2022-003262. doi: 10.1136/ejhpharm-2022-003262. Online ahead of print.

ABSTRACT

OBJECTIVE: The aim of this study was to investigate the prevalence and severity of potential drug-drug interactions (pDDIs) in hospitalised patients with major psychiatric disorders and to identify factors associated with their occurrence.

METHODS: The research was designed as an observational, cross-sectional study conducted at the Clinic for Mental Disorders (CMD) 'Dr. Laza Lazarevic', Belgrade, Serbia. Medscape, Epocrates and Lexicomp bases were used to detect potential drug interactions among inpatients. Multivariate regression analysis was used to reveal risk and protective factors associated with the number of pDDIs.

RESULTS: The study included 511 patients, average age 44.63±11.81 years. The average number of pDDIs per patient ranged from 5.9±4.7 (Medscape) to 8.2±5.4 (Epocrates) and 8.5±5.1 (Lexicomp). The following risk factors were identified by all three interaction checkers used: C-reactive protein, number of pharmacological subgroups, number of prescribed drugs, antibiotics, antacids, vitamins, number of associated comorbidities, route, form and dose of the drug.

CONCLUSIONS: When making clinical decisions to reduce drug problems, including DDIs, one should consult several interaction databases, which should be reviewed by a multidisciplinary team consisting of an experienced clinical pharmacist, physician, nurse, and so on.

PMID:35728951 | DOI:10.1136/ejhpharm-2022-003262

Cochrane Database Syst Rev. 2022 Jun 21;6:CD006404. doi: 10.1002/14651858.CD006404.pub4.

ABSTRACT

BACKGROUND: The World Health Organization (WHO) recommends artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria. Concerns about artemisinin resistance have led to global initiatives to develop new partner drugs to protect artemisinin derivatives in ACT. Pyronaridine-artesunate is a novel ACT.

OBJECTIVES: To evaluate the efficacy of pyronaridine-artesunate compared to alternative ACTs for treating people with uncomplicated P falciparum malaria, and to evaluate the safety of pyronaridine-artesunate and other pyronaridine treatments compared to alternative treatments.

SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; Embase; and LILACS. We also searched ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, and the ISRCTN registry for ongoing or recently completed trials. The date of the last search was 27 October 2021.

SELECTION CRITERIA: For the efficacy analysis, we included randomized controlled trials (RCTs) of pyronaridine-artesunate for treating uncomplicated P falciparum malaria. For the safety analysis, we included RCTs that used pyronaridine alone or in combination with any other antimalarials. In addition to these analyses, we conducted a separate systematic review summarizing data on safety from non-randomized studies (NRS) of any patient receiving pyronaridine (NRS safety review). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data and assessed the certainty of the evidence. We meta-analysed data to calculate risk ratios (RRs) for treatment failures between comparisons, and for safety outcomes between and across comparisons.

MAIN RESULTS: We included 10 relevant RCTs. Seven RCTs were co-funded by Shin Poong Pharmaceuticals, and three were funded by government agencies. Efficacy analysis (RCTs) For the efficacy analysis, we identified five RCTs comprising 5711 participants. This included 4465 participants from 13 sites in Africa, and 1246 participants from five sites in Asia. The analysis included 541 children aged less than five years. Overall, pyronaridine-artesunate had a polymerase chain reaction (PCR)-adjusted treatment failure rate of less than 5%. We evaluated pyronaridine-artesunate versus the following. • Artemether-lumefantrine. Pyronaridine artesunate may perform better for PCR-adjusted failures at day 28 (RR 0.59, 95% confidence interval (CI) 0.26 to 1.31; 4 RCTs, 3068 participants, low-certainty evidence); for unadjusted failures at day 28 (RR 0.27, 95% CI 0.13 to 0.58; 4 RCTs, 3149 participants, low-certainty evidence); and for unadjusted failures at day 42 (RR 0.61, 95% CI 0.46 to 0.82; 4 RCTs, 3080 participants, low-certainty evidence). For PCR-adjusted failures at day 42, there may be little or no difference between groups (RR 0.86, 95% CI 0.49 to 1.51; 4 RCTs, 2575 participants, low-certainty evidence). • Artesunate-amodiaquine. Pyronaridine artesunate may perform better for PCR-adjusted failures at day 28 (RR 0.55, 95% CI 0.11 to 2.77; 1 RCT, 1245 participants, low-certainty evidence); probably performs better for unadjusted failures at day 28 (RR 0.49, 95% CI 0.30 to 0.81; 1 RCT, 1257 participants, moderate-certainty evidence); may make little or no difference for PCR-adjusted failures at day 42 (RR 0.98, 95% CI 0.20 to 4.83; 1 RCT, 1091 participants, low-certainty evidence); and probably makes little or no difference for unadjusted failures at day 42 (RR 0.98, 95% CI 0.78 to 1.23; 1 RCT, 1235 participants, moderate-certainty evidence). • Mefloquine plus artesunate. Pyronaridine artesunate may perform better for PCR-adjusted failures at day 28 (RR 0.37, 95% CI 0.13 to 1.05; 1 RCT, 1117 participants, low-certainty evidence); probably performs better for unadjusted failures at day 28 (RR 0.36, 95% CI 0.17 to 0.78; 1 RCT, 1120 participants, moderate-certainty evidence); may make little or no difference for unadjusted failures at day 42 (RR 0.84, 95% CI 0.54 to 1.31; 1 RCT, 1059 participants, low-certainty evidence); but may lead to higher PCR-adjusted failures at day 42 (RR 1.80, 95% CI 0.90 to 3.57; 1 RCT, 1037 participants, low-certainty evidence). Safety analysis (RCTs) For the RCT safety analysis, we identified eight RCTs, one of which was delineated by study site, comparing pyronaridine-artesunate to other antimalarials. Pyronaridine-artesunate was associated with raised liver enzymes compared to other antimalarials: alanine aminotransferase (ALT) (RR 3.59, 95% CI 1.76 to 7.33; 8 RCTS, 6669 participants, high-certainty evidence) and aspartate transaminase (AST) (RR 2.22, 95% CI 1.12 to 4.41; 8 RCTs, 6669 participants, moderate-certainty evidence). No such effect was demonstrated with bilirubin (RR 1.03, 95% CI 0.49 to 2.18; 7 RCTs, 6384 participants, moderate-certainty evidence). There was one reported case in which raised ALT occurred with raised bilirubin. No study reported severe drug-induced liver injury. Electrocardiograph (ECG) abnormalities were less common with pyronaridine-artesunate compared to other antimalarials. We identified no other safety concerns. NRS safety review A review on safety in NRS allowed us to increase the population within which safety was assessed. We included seven studies with 9546 participants: five single-arm observational studies, one cohort event monitoring study, and one dose-escalation study. All studies provided data on adverse event frequency, with a small number of participants experiencing serious adverse events and adverse effects related to pyronaridine: serious adverse events average 0.37%; drug-related 9.0%. In two studies reporting elevations in liver enzymes, small percentages of participants (2.4% and 14.1% respectively) experienced increases in either ALT, AST, or bilirubin on day 7; however, these were small increases that returned to normal by day 42. AUTHORS' CONCLUSIONS: Pyronaridine-artesunate was efficacious against uncomplicated P falciparum malaria; achieved a PCR-adjusted treatment failure rate of less than 5% at days 28 and 42; and may be at least as good as, or better than, other marketed ACTs. Pyronaridine-artesunate increases the risk of episodes of abnormally raised ALT. The observational data did not signal an excess of clinically important adverse effects.

PMID:35726133 | DOI:10.1002/14651858.CD006404.pub4

Sci Rep. 2022 Jun 20;12(1):10317. doi: 10.1038/s41598-022-13894-8.

ABSTRACT

Current methods of pharmacovigilance result in severe under-reporting of adverse drug events (ADEs). Patient forums have the potential to complement current pharmacovigilance practices by providing real-time uncensored and unsolicited information. We are the first to explore the value of patient forums for rare cancers. To this end, we conduct a case study on a patient forum for Gastrointestinal Stromal Tumor patients. We have developed machine learning algorithms to automatically extract and aggregate side effects from messages on open online discussion forums. We show that patient forum data can provide suggestions for which ADEs impact quality of life the most: For many side effects the relative reporting rate differs decidedly from that of the registration trials, including for example cognitive impairment and alopecia as side effects of avapritinib. We also show that our methods can provide real-world data for long-term ADEs, such as osteoporosis and tremors for imatinib, and novel ADEs not found in registration trials, such as dry eyes and muscle cramping for imatinib. We thus posit that automated pharmacovigilance from patient forums can provide real-world data for ADEs and should be employed as input for medical hypotheses for rare cancers.

PMID:35725736 | DOI:10.1038/s41598-022-13894-8

BMC Cardiovasc Disord. 2022 Jun 20;22(1):280. doi: 10.1186/s12872-022-02724-4.

ABSTRACT

BACKGROUND: Neuropsychiatric side effects of cardiac drugs such as nervousness, mood swings and agitation may be misinterpreted as symptoms of anxiety. Anxiety in cardiac patients is highly prevalent and associated with poor outcomes, thus an accurate identification is essential. The objectives were to: (I) describe the possible neuropsychiatric side effects of common cardiac drug therapies, (II) describe the use of cardiac drug therapy in cardiac patients with self-reported symptoms of anxiety compared to those with no symptoms of anxiety, and (III) investigate the association between the use of cardiac drug therapy and self-reported symptoms of anxiety.

METHODS: DenHeart is a large national cross-sectional survey combined with national register data. Symptoms of anxiety were measured by the Hospital Anxiety and Depression Scale (HADS-A) on patients with ischemic heart disease, arrhythmia, heart failure and heart valve disease. Side effects were obtained from 'product summaries', and data on redeemed prescriptions obtained from the Danish National Prescription Registry. Multivariate logistic regression analyses explored the association between cardiac drug therapies and symptoms of anxiety (HADS-A ≥ 8).

RESULTS: Among 8998 respondents 2891 (32%) reported symptoms of anxiety (HADS-A ≥ 8). Neuropsychiatric side effects were reported from digoxin, antiarrhythmics, beta-blockers, ACE-inhibitors and angiotensin receptor antagonists. Statistically significant higher odds of reporting HADS ≥ 8 was found in users of diuretics, lipid-lowering agents, nitrates, antiarrhythmics and beta-blockers compared to patients with no prescription.

CONCLUSION: Some cardiac drugs were associated with self-reported symptoms of anxiety among patients with cardiac disease. Of these drugs neuropsychiatric side effects were only reported for antiarrhythmics and beta-blockers. Increased awareness about the possible adverse effects from these drugs are important.

PMID:35725383 | DOI:10.1186/s12872-022-02724-4

Eur J Cancer. 2022 Jun 17;172:1-12. doi: 10.1016/j.ejca.2022.05.024. Online ahead of print.

ABSTRACT

PURPOSE: Many intratumoural (IT) immunotherapies are currently developed in the clinic with the aim of overcoming primary and secondary resistance and/or to limit on-target/off-tumour toxicities of immune checkpoint targeted therapies. This study aimed to describe the feasibility, safety and efficacy of IT immunotherapy treatments.

DESIGN: This retrospective single-centre study included the first 100 consecutive patients enrolled in Gustave Roussy's Human IntraTumoral-ImmunoTherapy (HIT-IT) program. Patient characteristics, target description, image guidance, safety and response according to iRECIST (Response Evaluation Criteria in Solid Tumours for immunotherapy trials) were recorded. Predictive factors of complications and responses were analysed. Survival was also reported.

RESULTS: From 09/2015 to 05/2020, 100 patients had 115 tumours injected during 423 treatment cycles. Most frequent primary tumour arose from the skin (n = 49), digestive track (n = 4) or head and neck (n = 8). Injected tumours' mean diameter was 37 ± 23 mm, and a median number of 4 IT injections per patient (interquartile range:3-5) were performed. Targeted tumours for IT injections were superficial lymph nodes (36.5%), subcutaneous lesions (25.2%), liver tumours (20.9%) and others (17.4% including tumour sites such as deep lymph nodes or lung). Most patients (72%) received systemic immunotherapy in combination with HIT-IT. Procedure- and drug-related adverse events (AEs) occurred in 11.3% and 33.3% of the treatment cycles, respectively. Only 3 procedure-related AEs were grade-3 (0.7%); and no grade-4 or 5 occurred. Among all cycles, 7 grade-3 and 1 grade-5 drug-related AEs were reported. Complete and partial responses were achieved for 5% and 18% of patients, respectively, while stable disease was the best response for 11%. Patients receiving HIT-IT as a 1st-line treatment (24%), or not previously pre-treated with immunotherapy (53%) responded better, p = 0.001 and p = 0.004, respectively. From 1st cycle of IT, 12-month overall progression-free survival and overall survival were 21% (14-31%) and 57% (47-68%), respectively.

CONCLUSIONS: This retrospective study, conducted on patients with cancer and treated within clinical trials at Gustave Roussy, demonstrates the feasibility and safety of the IT immunotherapy strategy.

PMID:35724442 | DOI:10.1016/j.ejca.2022.05.024

J Cosmet Dermatol. 2022 Jun 20. doi: 10.1111/jocd.15171. Online ahead of print.

ABSTRACT

BACKGROUND: The combined use of oral isotretinoin with energy-based interventions including fractional microneedle radiofrequency, pulsed dye laser, and ablative fractional laser is an effective way to treat moderate-to-severe inflammatory acne lesions. However, studies regarding its efficacy and safety are limited.

AIMS: This study aimed to assess the efficacy and safety of a treatment using low-dose isotretinoin with energy-based interventions for inflammatory acne.

PATIENTS AND METHODS: This retrospective cohort study included 126 patients who were diagnosed with inflammatory acne and were treated with systemic isotretinoin for at least 3 months. Patients were divided into EBD (energy-based intervention) (n=82) and non-EBD groups (n=44). Clinical outcomes of both groups were assessed using medical records and digital photographs.

RESULTS: After treatment, the modified Global Acne Grading Score of the EBD and non-EBD groups decreased by 35.1±17.2 and 25.6±10.1, respectively. The improvement in acne severity was significantly greater in the EBD group than in the non-EBD group. Cumulated isotretinoin dose and frequency of drug-related side effects were significantly higher in the non-EBD group than in the EBD group.

CONCLUSION: Combined treatment with low-dose isotretinoin and energy-based intervention is well tolerated and associated with positive responses in patients with inflammatory acne.

PMID:35723897 | DOI:10.1111/jocd.15171

Xenobiotica. 2022 Jun 20:1-23. doi: 10.1080/00498254.2022.2092783. Online ahead of print.

ABSTRACT

The recommended treatment regimen for tuberculosis is a combination of agents with antitubercular activity, during which hepatotoxicity is one of the most common side effects. In addition to the N-acetyltransferase 2 (NAT2) genotype, rs3814055 in nuclear receptor subfamily 1, group I, member 2 (NR1I2) has been demonstrated to be associated with anti-tuberculosis drug-induced hepatotoxicity (ATDH), but previous results have been inconsistent.A retrospective nested hospital-based case-control study was performed to investigate the association between genetic polymorphisms and the risk of ATDH. Fifteen genetic variants (13 SNPs and two null genotypes) in cytochrome P450 2E1, NR1I2, UDP-glucuronosyltransferase 1A1, NAT2, superoxide dismutase 1, superoxide dismutase 2, and glutathione S-transferases (GSTT1, GSTM1, GSTP1) were genotyped. Odds ratios with 95% confidence intervals were calculated with drug doses, body mass index comorbidity of diabetes mellitus, and baseline alanine transaminase value as covariates.Conditional logistic regression demonstrated that the NAT2 slow acetylation genotype and the T allele of rs3814055 in NR1I2 may contribute to susceptibility to ATDH.Stratified association analysis demonstrated that in NAT2 non-slow acetylators, the T allele of rs3814055 was a risk factor for ATDH, whereas the T allele did not increase the susceptibility to ATDH in slow acetylators.

PMID:35723590 | DOI:10.1080/00498254.2022.2092783

Neuro Oncol. 2022 Jun 20:noac155. doi: 10.1093/neuonc/noac155. Online ahead of print.

ABSTRACT

BACKGROUND: Approximately 70% of lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in accumulation of oncometabolite D-2-hydroxyglutarate (D-2-HG); this leads to epigenetic dysregulation, oncogenesis, and subsequent clonal expansion. DS-1001 is an oral brain-penetrant mutant IDH1 selective inhibitor. This first-in-human study investigated the safety, pharmacokinetics, pharmacodynamics, and efficacy of DS-1001.

METHODS: This was a multicenter, open-label, dose-escalation, phase I study of DS-1001 for recurrent/progressive IDH1-mutant (R132) glioma (N = 47) (NCT03030066). DS-1001 was administered orally at 125-1400 mg twice daily. Dose escalation used a modified continual reassessment method.

RESULTS: The maximum tolerated dose was not reached. Eight patients were continuing treatment at the data cut-off. Most adverse events (AEs) were grade 1-2. Twenty patients (42.6%) experienced at least one grade 3 AE. No grade 4 or 5 AEs or serious drug-related AEs were reported. Common AEs (>20%) were skin hyperpigmentation, diarrhea, pruritus, alopecia, arthralgia, nausea, headache, rash, and dry skin. The objective response rates were 17.1% for enhancing tumors and 33.3% for non-enhancing tumors. Median progression-free survival was 10.4 months (95% confidence interval [CI], 6.1 to 17.7 months) and not reached (95% CI, 24.1 to not reached) for the enhancing and non-enhancing glioma cohorts, respectively. Seven on-treatment brain tumor samples showed a significantly lower amount of D-2-HG compared with pre-study archived samples.

CONCLUSIONS: DS-1001 was well-tolerated with a favorable brain distribution. Recurrent/progressive IDH1-mutant glioma patients responded to treatment. A study of DS-1001 in patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 glioma is ongoing (NCT04458272).

PMID:35722822 | DOI:10.1093/neuonc/noac155

Cureus. 2022 May 15;14(5):e25028. doi: 10.7759/cureus.25028. eCollection 2022 May.

ABSTRACT

We present a unique case of a 60-year-old male with congestive heart failure who was admitted for a pre-syncopal episode and found to be in atrial fibrillation with rapid ventricular response (RVR). In order to effectively rate control the patient, he was administered an amiodarone bolus and intravenous (IV) infusion over 24 hours, along with a single oral 200 mg dose the following day. The patient subsequently developed acute hepatotoxicity along with features of acute kidney injury (AKI), pulmonary distress, and leukocytosis. After ruling out other etiologies for acute liver, pulmonary, and kidney injury, amiodarone-induced multi-organ toxicity was suspected and amiodarone was discontinued. Within hours of amiodarone discontinuation, the patient's clinical status and organ function improved remarkably. In the setting of a patient being treated with IV amiodarone and presenting with sudden signs of dyspnea, acute elevation of transaminases and AKI within one to two days of initial dosing, acute amiodarone-induced organ toxicity should be considered.

PMID:35719804 | PMC:PMC9199562 | DOI:10.7759/cureus.25028

Int J Rheum Dis. 2022 Jun 19. doi: 10.1111/1756-185X.14371. Online ahead of print.

ABSTRACT

AIM: Macrophage activation syndrome (MAS), a severe complication of systemic adult-onset Still's disease (AOSD), has been reported to occur during interleukin-6 (IL-6) inhibitor treatment. However, predictors for MAS development are unknown. Therefore, this study investigated predictive features for MAS development after starting IL-6 inhibitor treatment in systemic AOSD patients.

METHOD: In a single-center retrospective study involving systemic AOSD patients who were refractory to high-dose glucocorticoids with immunosuppressants and started IL-6 inhibitor treatment between April 2008 and March 2020, we compared the baseline clinical features between patients who developed AOSD flare with MAS features (MAS group) and those who did not (non-MAS group) during IL-6 inhibitor treatment.

RESULTS: Only tocilizumab was used as an IL-6 inhibitor. Six of 14 refractory systemic AOSD patients developed AOSD flares with MAS features during tocilizumab treatment, including 4 who developed them shortly after initiation. The MAS group had significantly lower neutrophil counts, fibrinogen, and higher IL-18/C-reactive protein (CRP) ratio at starting tocilizumab (baseline) than the non-MAS group. Before starting tocilizumab, neutrophil counts were trending downward and upward in the MAS and non-MAS groups, respectively, with significant differences in changes. Receiver operating characteristic analysis showed that baseline neutrophil counts and fibrinogen and their changes before tocilizumab treatment and baseline IL-18/CRP ratio had significant discriminatory abilities for subsequent MAS development.

CONCLUSION: We identified baseline laboratory features associated with MAS development after initiating an IL-6 inhibitor in refractory systemic AOSD patients. These features may reflect the suppression of IL-6 signaling, and further suppression of IL-6 signaling might trigger early-onset MAS.

PMID:35719030 | DOI:10.1111/1756-185X.14371

Anticancer Agents Med Chem. 2022 Jun 17. doi: 10.2174/1871520622666220617103126. Online ahead of print.

ABSTRACT

Background-Renal cell carcinoma (RCC) is a diverse collection of malignancies with varying histological characteristics, molecular changes, prognosis, and therapeutic response. Tivozanib was first approved in March 2021, by USFDA with the brand name of Fotivda. Tivozanib hydrochloride monohydratesis an oral medication that is used to treat relapsed or refractory renal cell carcinoma. Objective-In this review, we explain renal cell carcinomaand its different treatments by the anti-renal carcinoma drugs. Methods-A comprehensive literature search was conducted in the relevant databases like ScienceDirect, PubMed, ResearchGate, and Google Scholar to identify studies. Conclusion- Tivozanib is an oral VEGFR-1, VEGFR-2, and VEGFR-3 tyrosine kinase inhibitor that is extremely selective and powerful. It has much less affinity for other receptor tyrosine kinase than other multitargeted TKIs now in clinical use. Because of its long half-life in circulation, it may be able to block VEGFRs more consistently. Dose-related controllable hypertension was the most commonly seen drug-related side event. Fatigue, hoarseness, and diarrhea, which were all common side effects, were not dose-related. Because of its target specificity, tivozanib can work well with other medications that have low side effects. Blocking both the VEGF and mTOR signaling pathways at the same time has the benefit of providing synergistic antitumor efficacy while also preventing treatment resistance. Therefore, in overall summary, we can say that the drug tivozanib is suitable for treatment in patients with renal cell carcinoma with multi-center clinical trials.

PMID:35718972 | DOI:10.2174/1871520622666220617103126

Zhongguo Zhong Yao Za Zhi. 2022 May;47(10):2557-2564. doi: 10.19540/j.cnki.cjcmm.20220211.601.

ABSTRACT

Traditional Chinese medicine(TCM) has made outstanding contributions to disease prevention and treatment, survival, and reproduction of the Chinese nation. Currently, the inheritance and innovative development of TCM have become a national strategy. However, in recent years, adverse reactions/events of Chinese medicine frequently occurred. In particular, in terms of the safety problem of newly discovered &quot;toxic&quot; Chinese medicine, it is often difficult to answer the question scientifically and develop effective solutions. When facing international public opinions and public questioning, they are often &quot;passively criticized&quot;. To solve the difficult problem about the safety of Chinese medicine, we urgently need to make breakthroughs in the cognition of toxicity of Chinese medicine and prevention and control of risks. This research team has been committed to the research on the safety of Chinese medicine for the long term. In particular, in terms of safety evaluation and risk prevention and control of newly discovered &quot;toxic&quot; Chinese medicine, they have made a series of original discoveries. On the basis of the discoveries, they innovated the cognition theory and methods of the toxicity of Chinese medicine, opened up a new field of research on the idiosyncratic toxicity and indirect toxicity of Chinese medicine, and proposed and established the disease-syndrome-based toxicology(DSBT), the model and method of safety evaluation of Chinese medicine related to diseases and syndromes. In light of the theory and methods of DSBT which have been applied to the objective eva-luation and analysis of the mechanism of the hepatotoxicity of Chinese medicine such as Polygoni Multiflori Radix, the mechanism hypothesis of &quot;toxicity due to three causes&quot; of idiosyncratic hepatotoxicity of Chinese medicine was proposed and confirmed. The findings revealed that the substances that induced idiosyncratic or indirect toxicity in Chinese medicine often did not possess definite direct toxi-city. Therefore, this research team proposed the concept of toxicity-related substances(TRS) in Chinese medicine. Based on the mo-dern scientific cognition of toxicity of Chinese medicine, the team proposed the strategy and method of Chinese medicine compatibility to reduce the toxicity based on the component-effect-target interaction to underpin the demonstration of the scientific connotation of toxicity and side effects of &quot;toxic&quot; Chinese medicine and establishment of scientific and effective risk prevention and control strategies. In light of the innovative development of toxicity cognition of Chinese medicine, this study is expected to provide important theoretical guidance and methodological support for scientific evaluation and precise prevention and control of the safety risk of &quot;toxic&quot; Chinese medicine.

PMID:35718473 | DOI:10.19540/j.cnki.cjcmm.20220211.601

Neurochem Int. 2022 Jun 16:105380. doi: 10.1016/j.neuint.2022.105380. Online ahead of print.

ABSTRACT

One of the most significant threats in Parkinson's disease (PD) is neurodegeneration. Neurodegeneration at both nigral as well as non-nigral regions of the brain is considered responsible for disease progression in PD. The key factors that initiate neurodegeneration are oxidative stress, neuroinflammation, mitochondrial complex-1 inhibition, and abnormal α-synuclein (SNCA) protein aggregations. Nigral neurodegeneration results in motor symptoms (tremor, bradykinesia, rigidity, shuffling gait, and postural instability) whereas; non-nigral neurodegeneration is responsible for non-motor symptoms (depression, cognitive dysfunctions, sleep disorders, hallucination, and psychosis). The available therapies for PD aim at increasing dopamine levels. The medications such as Monoamine oxidase B (MAO-B) inhibitors, catechol o-methyltransferase (COMT) inhibitors, Dopamine precursor (Levodopa), dopamine agonists, and dopamine reuptake inhibitors drastically improve the motor symptoms and quality of life only in the early stages of the disease. However, dopa resistant motor symptoms (abnormality in posture, speech impediment, gait, and balance problems), dopa resistant non-motor signs (sleep problems, autonomic dysfunction, mood, and cognitive impairment, pain), and drug-related side effects (motor fluctuations, psychosis, and dyskinesias) are considered responsible for the failure of these therapies. Further, none of the treatments, alone or in combination, are capable of halting the disease progression in the long run. Therefore, there is a need to develop safe and efficient neuroprotective agents, which can slow or stop the disease progression for the better management of PD. In this review, an effort has been made to discuss the various mechanisms responsible for progressive neurodegeneration (disease progression) in PD and also multiple strategies available for halting disease progression.

PMID:35718278 | DOI:10.1016/j.neuint.2022.105380

J Biomed Nanotechnol. 2022 Mar 1;18(3):660-676. doi: 10.1166/jbn.2022.3297.

ABSTRACT

Hepatocellular carcinoma (HCC), due to the lack of efficient diagnostic methods and short of available treatments, becomes the third main cause of cancer deaths. Novel treatments for HCCs are thus in great need. The fast-growing area of drug delivery provides intriguing possibility to design nanocarriers with unique properties. The nanocarriers performanced as drug deliver vehicles enable the design of diverse drug delivery systems, which could serve multiple purposes, including improved bioavailability, controlled or triggered release and targeted delivery, leading to enhanced drug efficacy and lowered drug toxicity. This paper provides an overview on the types of delivery vehicles, functions of drug nanocarriers and types of ligand-based targeting systems and highlights the advances made towards better HCC treatments.

PMID:35715919 | DOI:10.1166/jbn.2022.3297